Synergetic preparation for treating cardiovascular diseases, diabetes mellitus and hepatobiliary diseases. RU patent 2493841.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a synergetic preparation for treating cardiovascular insufficiency, types I and II diabetes mellitus, hepatobiliary diseases, containing a combination of a pharmaceutically acceptable salt of 2-ethyl-6-methyl-3-pyridin-3-ole and taurin in the amount of 2-75% and pharmaceutically acceptable carriers, excipients and additives with the mass ratio of the active ingredients of the combination making 9:1 to 1:9. The preparation may be presented in the form of a tablet, a capsule or a solution for injections. The invention also refers to a method of treating cardiovascular insufficiency, types I and II diabetes mellitus, hepatobiliary diseases wherein the therapeutically effective amount of the synergetic preparation is administered to the patient.

EFFECT: preparations possess the higher efficacy as compared to the common analogues.

5 cl, 7 tbl, 7 ex

The technical field to which the invention relates

The invention relates to medicine and pharmacology. More specifically, the invention provides a synergistic products containing pharmaceutically acceptable salt of 2-ethyl-6-methyl-3-pyridine-3-ol and taurine for the treatment ofvascular insufficiency, diabetes types I and II, diseases of the hepatobiliary system, with improved pharmacological properties, in particular the increased efficiency.

The level of technology

In the patent RU 2054936 (publ. 27.02.1996) disclosed application of taurine as a membrane stabilizing means for treatment of patients with insulin dependent and non-insulin dependent diabetes mellitus. In the case of insulin-dependent diabetes reduction of the dose of insulin while taking only in 50% of cases was achieved perfect compensation of diabetes mellitus ( and ), improvement of General condition, decrease of weakness, pain in the lower extremities. When diabetes only two cases out of ten was achieved perfect compensation of the disease.

In the patent RU 2024256 (publ. 15.12.1994) disclosed application antihypertensive medication «» as a treatment for chronic diffuse liver diseases: chronic lane si and chronic active hepatitis, and biliary cirrhosis of the liver. Therapy in a dose of 1 g/day duration 21 days leads to a significant clinical improvement. However, the daily dose of 1 g, entered into during the month, can cause an allergic reaction to the drug and adversely affect blood clotting. With caution taurine appoint patients with increased secretion of gastric juice and persons under the age of majority, as well as on the initial stage, thyrotoxicosis and organic and functional changes in the Central and peripheral links of the Autonomous nervous system. As a result of the need to increase the daily dose of taurine can be problematic.

In the patent RU 2134109 (publ. 10.08.1999) disclosed method of treatment of patients with diabetes mellitus, comprising an introduction into the organism of the patient of insulin and/or drug and antioxidant, wherein the as an antioxidant use Mexidol, which is injected intramuscularly and/or orally once a day in the dose of 100-200 mg within 5-7 days treatment repeated every 3-4 months. Method allows to achieve the compensation of diabetes mellitus type I, remove insulin resistance and reduce the dose of insulin In patients with type diabetes method is effective in 70% of cases.

In the patent RU 2001616 (publ. 30.10.1993) disclosed agent for the treatment of cardiovascular insufficiency, including active active principle and filler - potato starch, gelatin, wherein, with the aim of increasing the specific activity, as the active beginning of the current use taufon, and as filling advanced - cellulose, Aerosil and stearinovokisly calcium in the following ratio of components, mass%:

taufon

82,7-84,09

potato starch

4,59-4,72

gelatin

1,77-2,2

microcrystalline cellulose

the 8.2-8,48

aeroforces

0,353-0,95

stearinovokisly calcium

0,71-1,3

In the patent RU 2144822 (publ. 27.01.2000) opened anti-ischemic and antiatherosclerotic tool «»containing Mexidol and auxiliary substances, wherein the ingredients are placed in a gelatin capsule when the content of Mexidol up to 50 wt.%. Preferably this composition has the composition (in wt.%):

Mexidol

50,0

potato starch

40,5-50,5

polivinilpirrolidon

2,4-2,8

magnesium stearinovokisly

0,9-1,1

talc

0,9-1,1

In the patent RU 2145855 (publ. 27.02.2000) disclosed anxiolytic, and way with Mexidol and auxiliary substances, wherein that the ingredients are placed in a gelatin capsule when the content of Mexidol from 30 to 60 wt.%. The preferred composition of such a composition (in wt.%):

Mexidol

30,0-60,0

potato starch

17,0-35,0

polivinilpirrolidon

2,5-3,5

magnesium stearinovokisly

0,8-1,2

microcrystalline cellulose

7,7-12,2

sugar dairy

12,0-18,0

The drug has anxiolytic, , antiamnestic, , activities and shortcomings of known drugs - derivatives benzodiazepinovogo series. The disadvantage of this drug is the presence of a significant number of dairy sugar, that impairs its use in diabetics.

In the patent RU 2205640 (publ. 10.06.2003) disclosed pharmaceutical composition containing Mexidol and excipients, characterized in that it additionally contains succinic acid of 0,5-5,0% of mass composition. Preferred options famous invention provide:

1) solution for injection containing components in the following ratio (mass%):

Mexidol

5,0-6,0

succinic acid

0,5-5,0

Trilon

0,0-0,2

water for injection

up to 100.

2) Granular powder for kapsulirovanija, contains components in the following ratio (mass%):

Mexidol

50,0-60,0

succinic acid

0,5-5,0

Trilon

0,0-0,2

pulp

25,0-35,0

starch

from 15.0-20.0

low-molecular polyvinylpyrrolidone

4,0-6,0

magnesium stearinovokisly

0,9-1,3

talc

0,8-1,1

3) Composition for tabletirovanija contains components in the following ratio (mass%):

Mexidol

50,0-60,0

succinic acid

0,5-5,0

Trilon

0,0-0,2

pulp

14,0-25,0

starch

15,0-25,0

low-molecular polyvinylpyrrolidone

4,0-6,0

sodium starch

0,0-5,0

magnesium stearinovokisly

0,8-1,0

talc

0,0-1,0

CL

0,0-3,0

Introduction of succinic acid and Trylon B ensures the stability of the medicinal forms of Mexidol for at least two years, and also absence of in medicinal forms, and improves their technological properties during manufacture.

However, it is known that the injection of disodium salt EDTA cause , as well as long-term or transient failure thyroid [Manual of Endocrinology and Metabolism. Fourth Edition. Ed. Lavin N. Lippincott Williams & Wilkins Publ. P.353]. In addition, article Kleinfeld M., Gross M «Electrocardiographic Manifestations of Hypocalcemia Produced With Ethylenediamine Tetraacetic Acid. J. Am. Physiol. Soc. Vol.187 No.31. (1956). P.479-482 on the model of rabbits was shown that injections of disodium salt EDTA lead to serious adverse changes in the ECG, in particular - to aberrant forms of waves So From studies in a rat model [Payne J.., Sansom .F. «The Susceptibility of Various Groups of Rats to Experimental Hypocalcaemia». J. Physiol. Vol.168 (1963). P.554-563] it follows that the life expectancy of fat animals with caused by intravenous infusion disodium salt EDTA be reduced by about 15% compared to animals of normal weight. Listed observations may serve as a basis for precaution when assigning a known drug.

In the application RU 2006146529 (publ. 20.07.2008) disclosed pharmaceutical composition, possessing neurotropic, antiamnestic, and activity, notable as active components contains Semax and Mexidol or pharmaceutically acceptable salts in therapeutically effective quantities. The preferred option it contains (in g):

Mexidol

0,4-5,0

Semax

0,0001-0,03

ammonium acetate

0,71

1 M acetic acid

to pH of 4,5-5,5

water for injection

up to 1 l

Method of obtaining of this composition suggests that the active ingredients or pharmaceutically acceptable salts dissolved in purified water and the resulting solution is subject liofilizatsii. Contraindications to the use of the substance of «Semax» are pregnancy, lactation period, acute psychosis (connected, in particular, alcohol and drugs) and convulsions in history, making it the use of alcohol or drug dependence patients unsafe.

In the patent RU 2380089 (publ. 10.10.2009) disclosed pharmaceutical composition for injection containing an aqueous solution of 2-ethyl-6-methyl-3- succinate and auxiliary substance, wherein it as a last contains sodium metabisulfite, the following ratio of components, mass%:

2-ethyl-6-methyl-3- succinate

5,0-6,0

sodium metabisulfite

0,05-1,25

water for injection

to 100.0

Introduction stabilizer - metabisulfita sodium allows to increase the shelf life of up to three years and more, improve the color settings solution while maintaining the basis of acute toxicity and the bioavailability of the drug. However, it is known [V. Madan, Walker S.L., Beck M.H. «Sodium metabisulfite allergy is common but is it relevant?» Contact Dermatitis. Vol.57. No.3 (2007). P.173-176; see also: The Food and Drug Administration. American Academy of Allergy, Asthma and Immunology. Reviewed by Luqman Seidu, MD on May 12, 2012 for WebMD.com]that the presence of metabisulfita sodium in the food, cosmetic and pharmaceutical products often causes allergic reactions. Thus, the introduction of this stabilizer imposes restrictions on the usage of popular drug.

In patent RU 2398583 (publ. 10.09.2010) opened an antioxidant and tool in the form of infusion solution that includes the 6-methyl-2-ethyl-3- succinate, sodium chloride, sodium hydroxide or hydrochloric acid and water for injection at the following component ratio (g/l):

6-methyl-2-ethyl-3- succinate

0,5-10,0

sodium chloride

8,0-10,0

sodium hydroxide or hydrochloric acid

to pH 4,0-7,0

water for injection

rest

However, from the description should not be the efficiency of application of known drug in diabetes mellitus, and diseases of the hepatobiliary system.

Thus, there is a need to expand the Arsenal of medicines for treatment of cardiovascular insufficiency, diabetes types I and II, diseases of the hepatobiliary system, with increased efficiency.

Disclosure of the invention

As a result of investigations the authors of the invention unexpectedly found that the inherent limitations of drugs known prior art can be overcome by the creation of synergy preparation containing pharmaceutically acceptable salt of 2-ethyl-6-methyl-3-pyridine-3-ol and taurine.

The invention provides a synergistic drug for the treatment of cardiovascular insufficiency, diabetes types I and II, diseases of the hepatobiliary system, which contains 2-75% combination of active ingredients, and a pharmaceutically acceptable carriers, fillers and auxiliary substances, the combination of active components consists of a pharmaceutically acceptable salt 2-ethyl-6-methyl-3-pyridine-3-ol and taurine mass ratio of 9:1 to 1:9.

The drug in accordance with the invention can be prepared in a solid or liquid forms. If the form is solid, the content of the combination of active ingredients, expressed in mass percent (wt.%). Alternatively, if the form is liquid, the content of the combination of active ingredients, expressed in mass-volume percentage (% wt./rpm.).

The expression «pharmaceutically acceptable salt of 2-ethyl-6-methyl-3-pyridine-3-ol ()is defined as any salt of 2-ethyl-6-methyl-3-pyridine-3-ol, suitable for the purposes of this invention and physiologically portable patient's body. Preferred examples of such salts are hydrochloride and succinate.

The solid form of presents tablets or capsules, preferably contain from 100 to 150 mg and from 300 to 250 mg of taurine. Pills may not necessarily be covered primarily to ensure their integrity during packing, transportation and storage. Preferably mass ratio pharmaceutically acceptable salt 2-ethyl-6-methyl-3-pyridine-3-ol and taurine is from 1 to 6.5 6.5:1.

The liquid form of presents with sterile solution for injection containing from 1 to 5%(wt./about.) and from 5% to 3% (wt./about.) taurine. Preferably, such a solution is placed in ampoules and contains 1.5% (wt./about.) and 3.5% (wt./about.) taurine.

The choice of pharmaceutically acceptable carriers, extenders and auxiliary substances for the preparation of appropriate forms is in the competence of the person skilled in the field of pharmacy and can be easily implemented in the course of a routine experiment. For example, for manufacture of tablets and capsules in accordance with the invention can be used cellulose, starch, polivinilpirrolidon, gelatin, magnesium stearate, calcium stearate, talc, aeroforces, etc. For the manufacture of solution for injection are suitable pyrogen-free water, sodium chloride, sodium acetate, acetic acid, hydrogen phosphates sodium etc. Sterilization solution for injection can be performed in any way precluding further deleterious effect on the organism of the patient. Preferably spend filtering.

The main areas of application of the drug in accordance with the invention, are the treatment of cardiovascular insufficiency, diabetes types I and II and diseases of the hepatobiliary system, such as biliary cirrhosis. However, the drug can be shown in acute and chronic violations of cerebral circulation and their consequences, discirkulatorna encephalopathy, dystonia, psychosomatic diseases, disorders and neurotic and plant with the manifestation of anxiety, fear, emotional voltage, memory disorders and attention, infringement of mental health, mental and neurologic diseases in the elderly, senile and/or diabetic cataract, cerebral atherosclerosis, in the complex treatment of acute pyoinflammatory processes in the abdominal cavity. The drug can be used in relieving alcohol or opiate withdrawal syndrome, acute intoxication neiroleptikami or poisoning of cardiac glycosides.

Realization of the invention

Next invention is illustrated by the examples of his preferred implementation.

Example 1. Tablets containing hydrochloride EMF and taurine

Prepare 5% (wt./about.) fountain solution mixing gelatin with distilled water. Conduct separate hydrochloride EMF, taurine, microcrystalline cellulose and potato starch through a sieve with a mesh size of 0,15 mm, Sift the components in the amounts indicated in table 1, mix for 30 minutes in the amalgamator with blades. The resulting mass in the same mixer at constant stirring sprayed with a hydrating solution to distribute moisture. The humidified weight granulated, passing through the granulator with a mesh size of 1.0 mm

Wet pellets are dried in a drying case at temperature 40 C to achieve a residual moisture content of 2-5%. Dried granules further subjected to dry granulation, which pass through the granulator with a mesh size of 1.0 mm, and then within 10 minutes magnesium to improve the yield strength of granules and reduce their adhesion.

Table 1

Component name

The contents of the component

Example 1A

Example 1B

Example 1B

mg

wt.%

mg

wt.%

mg

wt.%

Hydrochloride EMF

150

27,8

40

7,4

360

66,7

Taurine

250

46,3

360

66,7

40

7,4

Microcrystalline cellulose

75

13,9

75

13,9

75

13,9

Starch

60

11,1

60

11,1

60

11,1

Magnesium stearate

5

0,9

5

0,9

5

0,9

Weight pills mg

540

100,0

540

100,0

540

100,0

Example 2. Gelatine capsules, containing succinate EMF and taurine

Prepare 5% (wt./about.) fountain solution mixing gelatin with distilled water. Conduct separate succinate EMF, taurine, microcrystalline cellulose and potato starch through a sieve with a mesh size of 0,15 mm The sifted components, taken in the amounts indicated in table 2, the type specified in the same table the number of aerosol and stirred for 30 minutes in the amalgamator with blades. The resulting mass in the same mixer at constant stirring sprayed with a hydrating solution to distribute moisture. The humidified weight granulated, passing through the granulator with a mesh size of 1.0 mm

Wet pellets are dried in a drying case at temperature 40 C to achieve the residual moisture of 2-4%. Dried granules further subjected to dry granulation, which pass through the granulator with a mesh size of 1.0 mm, and then within 10 minutes magnesium to improve the yield strength of granules and reduce their adhesion. Granules repeatedly crushed, the resulting powder sift and fill them gelatinous capsules №2.

Table 2

Component name

The contents of the component

Example 2A

Example 2B

Example 2B

mg

wt.%

mg

wt.%

mg

wt.%

Succinate EMF

100

22,7

40

9,1

260

59,1

Taurine

200

45,5

260

59,1

40

9,1

Microcrystalline cellulose

70

15,9

70

15,9

70

15,9

Starch

58

13,2

58

13,2

58

13,2

Aeroforces

7

1,6

7

1,6

7

1,6

Magnesium stearate

5

1,1

5

1,1

5

1,1

Mass content, mg

445

100,0

440

100,0

440

100,0

Example 3. Solution for injection

In accordance with sanitary norms prepare glass device with a working volume of 0.8 l, equipped with a mixer, a thermometer and a bubbler. In device download 400-410 ml of water for injection with a temperature of 20-25°C, through bubbler serves nitrogen and at stirring make 8,1 g succinate EMF, achieve full dissolution, and then dissolve to 18.9 g of taurine.

To received transparent solution with stirring, add 5,2 g citrate (as pentahydrate) and 6.8 g citric acid. On reaching the full dissolution in the solution made 0.6 g of sodium chloride and the addition of 0.5 M hydrochloric acid to adjust pH, setting the value from 3.5 to 3.7. The volume of solution bring to a 500 ml and rinsed with nitrogen.

The received solution is transferred into a container for work under pressure. Creating the excessive pressure of nitrogen, the solution is passed through two series-connected filter-sterilizer with shut-off ability 1.0 microns and 0.2 microns prepared by the receiver. Sterile solution in a stream of nitrogen portions of 1 ml placed in the capsule, sealed and sterilized at 120°C for 15 minutes.

Table 3 shows the absolute and relative composition of the solution in an ampoule.

Table 3

Component name

The contents of the component

mg

% (mass./about.)

succinate EMF

8,1

1,50

taurine

18,9

3,50

citric acid

6,8

1,26

sodium citrate

5,2

0,96

sodium chloride

0,6

0,11

water for injection

500

92,66

100,00

Example 4. The cardioprotective effect

The cardioprotective action of the preparation in accordance with the invention, and taurine evaluated in experiments on male Wistar rats weighing 260-330 g, contained in conditions of 12/12 time the light conditions and treated with standard food and water ad libitum. Animals are divided into four groups of 9 individuals in each. Animals of the first group («control») intravenous isotonic saline solution. The second group of animals (taurine) receives intravenous injection solution of taurine in isotonic saline (20 mg/kg body weight). Animals of the third group («») intravenous succinate 2-ethyl-6-methylpyridine-3-ol (dose of 40 mg /kg body weight). In the fourth group («drug») animals receive the drug made in accordance with the example 3 (dose: 40 mg and 20 mg of taurine per kg body weight).

As a model for creating reversible myocardial ischemia and evaluation of the zone of myocardial form : the ends of ligatures, covering the coronary artery, conduct clearance in the plastic tube diameter of 1 mm and length is about 5-6 cm (RE 40), and then by moving the tube to the heart achieve occlusion of the left coronary artery, and in the opposite direction-reperfusion. During the experiment, the animals are kept on a the operating table, keeping the temperature of the body of the animal within 37,0±0.5 deg C.

Estimated size anatomical area of risk and infarction area is produced by the method of double-coloring dye blue Evans and chloride (TTC) (Mr Biomed., USA). After rendering the border between and departments heart of the rapidly removed and cut direction to the five fragments of the same thickness of 2 mm. Image basal surfaces five fragments photographed with a digital camera Olimpus 2020, connected with device microscope for the subsequent determination of the area of anatomical area of risk (Evans-negative plots) and infarction (Evans-positive plots). Area calculation is performed on the computer using Adobe Photoshop 4.0. The total amount of risk zones for every heart is calculated by multiplying the area Evans-negative plot of each slice to its thickness and summation of obtained four sections values. Then calculate the total amount of infarction area for the heart in the same way. Data on the size of the risk zones and myocardial present in the form of the ratio of the areas of risk to the total volume of the heart as well as in the form of the ratio of the infarction area and volume risk areas (percentage). Results are shown in table 4.

Table 4

Group

Size

areas of risk, %

infarction area, %

Control

48±4,1

62 ħ 3.8

Taurine

43±2,7

34±8,9

45±3,2

56±11,0

Drug

44±3,4

29±6,2

The lack of differences in the magnitude of the risk areas indicates a standard level of ligation of the left main coronary artery and equal initial conditions ischemia in all groups of animals. Protective action of the drug in accordance with the invention higher than that of taurine and succinate EMF that confirms the technical result of the invention.

Example 5. Hepatoprotective action

Male Wistar rats weighing 190-210 g divided into four groups according to 7 of animals in each. Before the start of the study animals of the control group (controls(0)») select a sample of blood, the accepted way to prepare blood serum and determine the activity of the alanine aminotransferase (Alt), aspartate aminotransferase (AST), alkaline phosphatase (ALP), using sets of Bio-la-test (produced by Pliva-Lachem Diagnostika S.R.O). Bilirubin determined spectrophotometrically. All the animals during the 4 days of subcutaneously administered by 0.4 ml of 50% solution (carbon tetrachloride, CCl 4 ) in a sterile sunflower oil.

Introduction of drugs rats realized once a day for 10 days with the help of gastric probe. Animals of the first group («control») have the aqueous suspension containing cellulose, starch, aeroforces, and magnesium stearate. Animals of the second group («taurine») force with a little water from the syringe imposed solution taurine the rate of 40 mg/kg body weight. Animals of the third group («») similarly imposed solution succinate EMF (dose: 20 mg/kg). Animals of the third group («drug») receive a suspension of the drug in accordance with the invention, prepared as described in examples 1 and 2.

After the experience of animals killed break the spine, prepared from the blood serum and determine the activity of enzymes and bilirubin level. The results are presented in table 5.

Table 5

Group

Indicator mmol/l

Alat

ASAT

ALP

Total bilirubin

Unconjugated bilirubin

Control (0)

1,15±0,24

1,37±0,26

8,4±0,7

11,02±0,74

4,38±1,01

Control

4,12±0,31

3,52±0,21

13,3±0,6

19,35±1,24

10,21±1,63

2,78±0,36

2,15±0,42

11,0±0,4

17,55±1,23

7,05±1,89

Taurine

3,59±0,52

2,33±1,25

9,7±0,4

16,63±2,31

8,79±2,14

Drug 1A

1,58±0,57

1,46±0,86

8,7±0,3

a 12.24±1,48

6,47±0,95

Drug 1B

2,39±0,42

1,75±0,68

8.9 ħ 0,4

14,41±1,50

7,42±0,84

Drug 2B

2,44±0,61

1,61±0,72

8,8±0,3

at 13.84±1,86

7,73±0,91

Drug 2B

1,76±0,49

1,84±0,72

9,1 approximately 0.5

13,49±1,51

5,83±1,01

Toxic liver damage in rats caused , leads to a significant increase in blood plasma of animals activity of enzymes Alt, AST and ALP, the increase of total and indirect bilirubin. Hepatoprotective action of the preparation in accordance with the invention significantly exceeds the efficiency as taurine and succinate EMF suspension, suggesting that the manifestation of synergies and confirms the technical result of the invention.

Example 6. Effect of the drug in diabetes mellitus

White rats weighing weighing 150-1900 g divided into 5 groups with 7 species. The first group («control(0)») drawn from intact animals, which intraperitoneally enter 1 ml/100 g of body mass apirogennoj to water. Animals of the second group («control») intraperitoneally injected at a dose of 135 mg/kg in the Third group of animals (taurine) receives solid gelatine capsules with powder taurine (100 mg). Animals of the fourth group («») in gelatinous capsules impose succinate 200 mg EMF («drug»). Animals of the fifth group («drug») give the capsules are made in accordance with examples 1A, 1B, 2A and 2B of the invention.

Table 6

Group

Spleen

Liver

DK

MD

DK

MD

Intact

71,8 ħ 4.9

50,3 ą1.5

227,1±19,4

241,3±21,6

Control

127,1±11,3

98,7±16,5

418,3±20,4

527,4±68,7

98,8±12,1

32,6±5,6

305,9±16,2

203,8±14,5

Taurine

99,4±7,7

43,7±13,2

337,2±30,1

224,5±31,6

Drug 1A

78,7 ħ 7.0

41,2±7,7

284,5±18,1

146,8±30,9

Drug 1B

81,6±8,1

36,3±6,8

291,7±17,4

133,5±28,1

Drug 2A

82,9±7,6

43,7±6,9

288,3±19,0

147,4±27,5

Drug 2B

85,3±8,1

38,4±7,3

302,6±16,8

151,7±24,2

Table 6 (continued)

Group

Kidney

Brain

Serum

DK

MD

DK

MD

MD

Intact

58,7±6,3

72,4±5,2

168,3±11,2

55,9±4,8

4,01±0,3

Control

83,6±10,9

77,6±12,3

297,7±20,1

109,4±15,8

4,27±0,2

38,5±4,3

37,2±6,9

186,5±9,9

26,1±4,1

3,4±0,1

Taurine

52,8±7,1

69,8±10,9

188,4±8,9

47,9±8,2

4,2±0,3

Drug 1A

59,1±5,3

71,7±6,2

169,7±11,2

39,6±11,2

3,9±0,1

Drug 1B

37,6±5,1

35,8±8,2

177,3±9,6

25,7±3,9

3,2±0,3

Drug 2A

61,3±4,7

75,1±5,9

172,4 ħ 9.8

41,0±10,3

4,1±0,2

Drug 2B

49,7 ħ 6.4

65,1±7,3

174,5±10,4

36,1±9,9

4,2±0,3

According to the results of the autopsies rats in all 5 groups calculate the indices of the mass of internal organs of diabetic lesions. In table 7 in the column «drug» presents data for a group of rats treated with therapy solid form, obtained in accordance with the example 1A of the invention.

Table 7

Bodies

The ratio of the mass of the groups:

Intact

Control

Taurine

Drug

Pituitary gland

3,58±0,27

4,98±0,61

4,80±0,37

4,39±0,33

4,05±0,27

Heart

4,01±0,06

4,59±0,24

4,05±0,17

4,35±0,21

3,98±0,18

Liver

3,11 ħ 0.09

4,37±0,17

3,95±0,16

3,52±0,19

3,15±0,19

Brain

5,38±0,20

5,77±0,22

7,01±0,40

6,64±0,27

5,99±0,33

Adrenal glands

1,43±0,11

2,44±0,26

2,13±0,27

2,12±0,42

1,62±0,11

Spleen

3,61±0,22

4,72±0,35

3,76±0,25

3,73±0,17

3,35±0,25

Thymus

0,98±0,12

0,82±0,07

1,11±0,24

0,56±0,11

1,08±0,24

Example 7. Assessment of nootropic action of the preparation in vivo no method of passive avoidance in a two-cell camera

A) Research on young individuals

When natural, especially when , aging in humans (for example, associated with Alzheimer's) most clearly and reliably had been a violation of memory, caused by the insufficient cholinergic system. Therefore neuroprotective action of the preparation in accordance with the invention was evaluated in a rat model of amnesia caused by the injection of scopolamine. In the experiment we used male rats at 6 months of age weighing 180-200,

Scopolamine was injected subcutaneously (2.5 mg/kg) for 30 minutes before training. Memory impairment was assessed by the usual method of passive avoidance in the two-section (dark, light) camera with painful learning in the dark compartment using the equipment of firm Lafayette, in (USA). Safety or memory impairment was assessed by the latent time spent in the bright (safe) compartment of the camera when playing reflex passive avoidance 24 hours after training or training with injection of scopolamine.

It is established that scopolamine causes amnesia 95% of trained animals, as evidenced by the entrance with a short latent period in the dark threat compartment when playing a reflex after 24 hours.

The drug in accordance with the invention has expressed antiamnesic action that is characterized by increase in the latency time of stay in the bright safe compartment camera. Long-term oral administration of the drug, prepared in accordance with examples 1A, 1B, 2A and 2B (30 mg/kg a day for 60 days) leads to the manifestation of antiamnesic effect of 78-82% of the animals.

B) Study on the old ones

For studies used a young, the elderly and old white rats Wistar of the age groups 6, 18 and 24 months, respectively. Memory disorder was estimated by the method of passive avoidance in the camera Location (USA) on the registration of latency time of a finding in a bright (safe) compartment of the camera when playing a reflex after 24 hours and 7 days after the training (getting painful irritation in the dark compartment).

In the control group of young animals after receiving pain irritation in the dark compartment camera consolidation reflex was observed in 92% of individuals (for a long time spent in safe lit compartment), and persisted in 86% of the individuals when playing reflex 7 days after the training.

In animals elderly (18 months) and in particular the old age (24 months), there was a sharp decline in memory. The transition into a dangerous dark compartment, where previously received pain, short latent period was observed in 73% and 87% of the animals respectively.

Oral administration of the drug, prepared in accordance with examples 1A, 1B, 2A and 2B (50 mg/kg a day for 60 days) leads to the manifestation of antiamnesic effect of 61-67% of older and 49-53% of older animals, that confirms the technical result of the invention.

1. Synergy drug for the treatment of cardiovascular insufficiency, diabetes types I and II, diseases of the hepatobiliary system, characterized in that it contains 2-75% combination of active ingredients, and a pharmaceutically acceptable carriers, fillers and excipients, this combination of active components consists of a pharmaceutically acceptable salt 2-ethyl-6-methyl-3-pyridine-3-ol and taurine mass ratio of 9:1 to 1:9.

3. Synergy drug according to claim 1, characterized in that it is presented in solid form in the form of capsules, and the mass ratio of pharmaceutically acceptable salt 2-ethyl-6-methyl-3-pyridine-3-ol and taurine is 6.5:1 to 1:6,5.

4. Synergy drug according to claim 1, characterized in that it is presented in a liquid form as a solution for injection, and the mass ratio of pharmaceutically acceptable salt 2-ethyl-6-methyl-3-pyridine-3-ol and taurine is 1:2,3.

5. The method of treatment of cardiovascular insufficiency, diabetes types I and II, diseases of the hepatobiliary system, characterized in that anyone in need of treatment, the patient is administered a therapeutically efficient quantity of the synergistic drug on any one of claims 1 to 4.